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Gene Review

a  -  nonagouti

Mus musculus

Synonyms: ASIP, ASP, Agouti coat color protein, Agouti switch protein, Agouti-signaling protein, ...
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Disease relevance of a


Psychiatry related information on a

  • Agouti yellow mice, with blocked melanocortin pathways, exhibited a significant depression of the hypercapnic sensitivity compared with weight-matched wild-type controls during non-rapid eye movement sleep (5.8 +/- 0.7 vs. 8.9 +/- 0.7 ml x min(-1) x %CO(2)(-1), P < 0.01), but not during wakefulness [6].
  • Consequently, although mahogany is broadly required for agouti peptide action, it also appears to be involved in the control of metabolic rate and feeding behavior independent of its suppression of agouti [7].
  • This gene is normally expressed in a manner consistent with a locus function, and, more importantly, its structure and expression are affected by a number of representative alleles in the agouti dominance hierarchy [8].

High impact information on a


Chemical compound and disease context of a

  • In agouti yellow (A(y)/a) mice, animals defective in pro-opiomelanocortin (POMC) signaling, normal levels of histamine, and t-MH were seen in the hypothalamus at 4 weeks of age when obesity had not yet developed [11].
  • The response of NPY-null mice to diet-induced obesity, chemically induced obesity (monosodium glutamate and gold thioglucose), and genetic-based obesity (lethal yellow agouti, Ay; uncoupling protein-diphtheria toxin transgenics, UCP-DT) were all normal [12].
  • VGF is required for obesity induced by diet, gold thioglucose treatment, and agouti and is differentially regulated in pro-opiomelanocortin- and neuropeptide Y-containing arcuate neurons in response to fasting [13].
  • Obese gene expression: reduction by fasting and stimulation by insulin and glucose in lean mice, and persistent elevation in acquired (diet-induced) and genetic (yellow agouti) obesity [14].
  • We have tested this hypothesis by examining agouti inhibition of both melanocortin-stimulated cyclic adenosine monophosphate production and the binding of a radioactive melanocortin analog in the murine B16F10 melanoma cell line [15].

Biological context of a


Anatomical context of a

  • Agouti, which is produced in the hair follicle, acts on follicular melanocytes to inhibit alpha-MSH-induced eumelanin production, resulting in the subterminal band of phaeomelanin often visible in mammalian fur [20].
  • Consequently, the obesity caused by ectopic expression of agouti in the lethal yellow (Ay) mouse may be due to the inhibition of melanocortin receptor(s) outside the hair follicle [20].
  • We have used a sensitive bioassay based on Xenopus melanophores to characterize pharmacologic properties of recombinant Agouti protein, and have directly measured its cell-surface binding to mammalian cells by use of an epitope-tagged form (HA-Agouti) that retains biologic activity [2].
  • The roles of melanocortin receptors or agouti-specific receptor(s) in agouti regulation of adipocyte metabolism and other peripheral effects remain to be determined [4].
  • This suggests that agouti expression in adipose tissue combined with hyperinsulinemia may lead to increased adiposity [4].

Associations of a with chemical compounds

  • Substitution of agouti residue Asp108 with alanine results in large increases in KI app for all three melanocortin receptors examined [19].
  • In addition, ASIP blocked the stimulatory effects of forskolin or dibutyryl cAMP, agents that act downstream from the MC1R, on tyrosinase activity and cell proliferation [21].
  • The direct cellular actions of Agouti include stimulation of fatty acid and triglyceride synthesis via a Ca(2+)-dependent mechanism [4].
  • A deletion in the first coding exon of the agouti gene was found associated with the proposed recessive allele of agouti in the darkly pigmented Standard Silver fox (aa) [22].
  • Neuronal histamine regulates food intake, adiposity, and uncoupling protein expression in agouti yellow (A(y)/a) obese mice [23].

Physical interactions of a


Enzymatic interactions of a


Regulatory relationships of a


Other interactions of a


Analytical, diagnostic and therapeutic context of a


  1. A biochemical function for attractin in agouti-induced pigmentation and obesity. He, L., Gunn, T.M., Bouley, D.M., Lu, X.Y., Watson, S.J., Schlossman, S.F., Duke-Cohan, J.S., Barsh, G.S. Nat. Genet. (2001) [Pubmed]
  2. Interaction of Agouti protein with the melanocortin 1 receptor in vitro and in vivo. Ollmann, M.M., Lamoreux, M.L., Wilson, B.D., Barsh, G.S. Genes Dev. (1998) [Pubmed]
  3. Mutations in the carboxyl terminus of the agouti protein decrease agouti inhibition of ligand binding to the melanocortin receptors. Kiefer, L.L., Ittoop, O.R., Bunce, K., Truesdale, A.T., Willard, D.H., Nichols, J.S., Blanchard, S.G., Mountjoy, K., Chen, W.J., Wilkison, W.O. Biochemistry (1997) [Pubmed]
  4. The yellow mouse obesity syndrome and mechanisms of agouti-induced obesity. Moussa, N.M., Claycombe, K.J. Obes. Res. (1999) [Pubmed]
  5. Agouti signal protein regulation in human melanoma cells. Voisey, J., Kelly, G., Van Daal, A. Pigment Cell Res. (2003) [Pubmed]
  6. Impact of interrupted leptin pathways on ventilatory control. Polotsky, V.Y., Smaldone, M.C., Scharf, M.T., Li, J., Tankersley, C.G., Smith, P.L., Schwartz, A.R., O'Donnell, C.P. J. Appl. Physiol. (2004) [Pubmed]
  7. Mahogany (mg) stimulates feeding and increases basal metabolic rate independent of its suppression of agouti. Dinulescu, D.M., Fan, W., Boston, B.A., McCall, K., Lamoreux, M.L., Moore, K.J., Montagno, J., Cone, R.D. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  8. Molecular characterization of the mouse agouti locus. Bultman, S.J., Michaud, E.J., Woychik, R.P. Cell (1992) [Pubmed]
  9. Transgenic expression of syndecan-1 uncovers a physiological control of feeding behavior by syndecan-3. Reizes, O., Lincecum, J., Wang, Z., Goldberger, O., Huang, L., Kaksonen, M., Ahima, R., Hinkes, M.T., Barsh, G.S., Rauvala, H., Bernfield, M. Cell (2001) [Pubmed]
  10. Epigenetic inheritance at the agouti locus in the mouse. Morgan, H.D., Sutherland, H.G., Martin, D.I., Whitelaw, E. Nat. Genet. (1999) [Pubmed]
  11. Hypothalamic neuronal histamine in genetically obese animals: its implication of leptin action in the brain. Itateyama, E., Chiba, S., Sakata, T., Yoshimatsu, H. Exp. Biol. Med. (Maywood) (2003) [Pubmed]
  12. Life without neuropeptide Y. Palmiter, R.D., Erickson, J.C., Hollopeter, G., Baraban, S.C., Schwartz, M.W. Recent Prog. Horm. Res. (1998) [Pubmed]
  13. VGF is required for obesity induced by diet, gold thioglucose treatment, and agouti and is differentially regulated in pro-opiomelanocortin- and neuropeptide Y-containing arcuate neurons in response to fasting. Hahm, S., Fekete, C., Mizuno, T.M., Windsor, J., Yan, H., Boozer, C.N., Lee, C., Elmquist, J.K., Lechan, R.M., Mobbs, C.V., Salton, S.R. J. Neurosci. (2002) [Pubmed]
  14. Obese gene expression: reduction by fasting and stimulation by insulin and glucose in lean mice, and persistent elevation in acquired (diet-induced) and genetic (yellow agouti) obesity. Mizuno, T.M., Bergen, H., Funabashi, T., Kleopoulos, S.P., Zhong, Y.G., Bauman, W.A., Mobbs, C.V. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  15. Agouti antagonism of melanocortin binding and action in the B16F10 murine melanoma cell line. Blanchard, S.G., Harris, C.O., Ittoop, O.R., Nichols, J.S., Parks, D.J., Truesdale, A.T., Wilkison, W.O. Biochemistry (1995) [Pubmed]
  16. The mouse lethal nonagouti (a(x)) mutation deletes the S-adenosylhomocysteine hydrolase (Ahcy) gene. Miller, M.W., Duhl, D.M., Winkes, B.M., Arredondo-Vega, F., Saxon, P.J., Wolff, G.L., Epstein, C.J., Hershfield, M.S., Barsh, G.S. EMBO J. (1994) [Pubmed]
  17. Induction of neuropeptide Y gene expression in the dorsal medial hypothalamic nucleus in two models of the agouti obesity syndrome. Kesterson, R.A., Huszar, D., Lynch, C.A., Simerly, R.B., Cone, R.D. Mol. Endocrinol. (1997) [Pubmed]
  18. Recombinant inbred strain and interspecific backcross analysis of molecular markers flanking the murine agouti coat color locus. Siracusa, L.D., Buchberg, A.M., Copeland, N.G., Jenkins, N.A. Genetics (1989) [Pubmed]
  19. Melanocortin receptor binding determinants in the agouti protein. Kiefer, L.L., Veal, J.M., Mountjoy, K.G., Wilkison, W.O. Biochemistry (1998) [Pubmed]
  20. Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Lu, D., Willard, D., Patel, I.R., Kadwell, S., Overton, L., Kost, T., Luther, M., Chen, W., Woychik, R.P., Wilkison, W.O. Nature (1994) [Pubmed]
  21. Agouti signaling protein inhibits melanogenesis and the response of human melanocytes to alpha-melanotropin. Suzuki, I., Tada, A., Ollmann, M.M., Barsh, G.S., Im, S., Lamoreux, M.L., Hearing, V.J., Nordlund, J.J., Abdel-Malek, Z.A. J. Invest. Dermatol. (1997) [Pubmed]
  22. A non-epistatic interaction of agouti and extension in the fox, Vulpes vulpes. Våge, D.I., Lu, D., Klungland, H., Lien, S., Adalsteinsson, S., Cone, R.D. Nat. Genet. (1997) [Pubmed]
  23. Neuronal histamine regulates food intake, adiposity, and uncoupling protein expression in agouti yellow (A(y)/a) obese mice. Masaki, T., Chiba, S., Yoshimichi, G., Yasuda, T., Noguchi, H., Kakuma, T., Sakata, T., Yoshimatsu, H. Endocrinology (2003) [Pubmed]
  24. Coupled site-directed mutagenesis/transgenesis identifies important functional domains of the mouse agouti protein. Perry, W.L., Nakamura, T., Swing, D.A., Secrest, L., Eagleson, B., Hustad, C.M., Copeland, N.G., Jenkins, N.A. Genetics (1996) [Pubmed]
  25. Interactions of alpha-melanotropin and agouti on B16 melanoma cells: evidence for inverse agonism of agouti. Siegrist, W., Drozdz, R., Cotti, R., Willard, D.H., Wilkison, W.O., Eberle, A.N. J. Recept. Signal Transduct. Res. (1997) [Pubmed]
  26. Regulation of leptin by agouti. Claycombe, K.J., Xue, B.Z., Mynatt, R.L., Zemel, M.B., Moustaid-Moussa, N. Physiol. Genomics (2000) [Pubmed]
  27. The melanocortin 1 receptor is the principal mediator of the effects of agouti signaling protein on mammalian melanocytes. Abdel-Malek, Z.A., Scott, M.C., Furumura, M., Lamoreux, M.L., Ollmann, M., Barsh, G.S., Hearing, V.J. J. Cell. Sci. (2001) [Pubmed]
  28. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Fan, W., Boston, B.A., Kesterson, R.A., Hruby, V.J., Cone, R.D. Nature (1997) [Pubmed]
  29. Agouti/melanocortin interactions with leptin pathways in obesity. Zemel, M.B. Nutr. Rev. (1998) [Pubmed]
  30. Modulation of melanogenic protein expression during the switch from eu- to pheomelanogenesis. Kobayashi, T., Vieira, W.D., Potterf, B., Sakai, C., Imokawa, G., Hearing, V.J. J. Cell. Sci. (1995) [Pubmed]
  31. Agouti structure and function: characterization of a potent alpha-melanocyte stimulating hormone receptor antagonist. Willard, D.H., Bodnar, W., Harris, C., Kiefer, L., Nichols, J.S., Blanchard, S., Hoffman, C., Moyer, M., Burkhart, W., Weiel, J. Biochemistry (1995) [Pubmed]
  32. Liver-specific expression of the agouti gene in transgenic mice promotes liver carcinogenesis in the absence of obesity and diabetes. Kuklin, A.I., Mynatt, R.L., Klebig, M.L., Kiefer, L.L., Wilkison, W.O., Woychik, R.P., Michaud, E.J. Mol. Cancer (2004) [Pubmed]
  33. Structure and function of ASP, the human homolog of the mouse agouti gene. Wilson, B.D., Ollmann, M.M., Kang, L., Stoffel, M., Bell, G.I., Barsh, G.S. Hum. Mol. Genet. (1995) [Pubmed]
  34. Molecular markers for the agouti coat color locus of the mouse. Lovett, M., Cheng, Z.Y., Lamela, E.M., Yokoi, T., Epstein, C.J. Genetics (1987) [Pubmed]
  35. Physical and genetic characterization of a 75-kilobase deletion associated with al, a recessive lethal allele at the mouse agouti locus. Barsh, G.S., Epstein, C.J. Genetics (1989) [Pubmed]
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